Conventional powder compositions used in DPIs and suspension based MDIs typically contain an active pharmaceutical agent that has been milled to a desired aerodynamic size. In a DPI, the active agent is generally admixed with a coarse carrier/diluent, such as lactose. Other additive materials may be presented to act as physical or chemical stabilizers, dispersants, taste masking agents, etc. In a suspension based MDI, the active agent is suspended in a low-boiling point liquid propellant. The propellant formulation may also include other materials which improve product performance, such as surfactants, etc.
There is a constant effort to improve upon the performance of existing inhalation delivery systems, including the performance of the compositions used in those systems. For example, the desire to improve the current particle based system to provide powders that can be effectively aerosolized to maintain a uniform dose and which can be easily separated from the carrier materials, so as to generate particles of a desired size for targeted site delivery in the pulmonary system, has in recent years, led to a considerable effort to engineer better inhaled particles. One goal of these efforts is the manufacture of particles which are chemically and physically more stable, have greater dispersion, aerosolization and cost efficiencies, so as to optimize inhalation aerosolization and delivery performance.
One alternative approach to size reduction by milling is spray-drying, which has been investigated with some success. Spray drying is a one-step continuous process which can directly produce particles of a desired size range. This approach is amenable to the production of drug powders for inhalation delivery, see, e.g. U.S. Pat. No. 4,590,206, Broadhead, J., et al, “Spray Drying of Pharmaceuticals”, Drug Development and Industrial Pharmacy, 18(11&12), 1169-1206 (1992), M. Sacchetti, M. Van Oort, Spray Drying and Supercritical Fluid Particle Generation Techniques, “Inhalation Aerosols: Physical and Biological Basis for Therapy”, Marcel Dekker, 1996, and patent publications WO 96/32149, WO 97/41833, WO 97/44013,WO 98/31346 and WO 99/16419.
Particles may be generated from solutions or suspensions. WO 96/09814 describes, for example, the spray drying of budesonide and lactose in ethanol, Published PCT application WO 2001/49263, U.S. Pat. Nos. 6,001,336, 5,976,574 (hydrophobic drugs from organic suspensions), and U.S. Pat. No. 7,267,813 (crystalline inhalable particles comprising a combination of two or more pharmaceutically active compounds) also describe spray dried particles.
While spray drying is suitable for producing respirable sized particles, solid state properties (particularly crystallinity) are difficult to control. The spray drying process, depending on whether solutions or suspensions are being sprayed, and the conditions under which the process occurs, may produce amorphous particles. Such amorphous spray dried particles may have physical and/or chemical stability problems and have an increased tendency to be hygroscopic, all of which are undesirable for pharmaceutical agents. Spray drying solutions having therapeutically active materials with or without excipients therein may produce amorphous material due to the rapid precipitation within the atomized droplets. Moreover, while crystalline materials may be produced, the resulting crystalline product may be of a kinetically preferred form, as opposed to the more thermodynamically stable form. Therefore, an undesirable polymorphic form may result. Further improvement in this area is desirable.
Obtaining crystalline materials reproducibly by spray drying is further complicated when multiple materials are being used, while one of the components may crystallize as desired, another in the same particle may not.
In recent years, attention has turned to nanoparticle drug delivery. Nanoparticles may afford certain advantages in inhaled therapies, particularly their increased rate of dissolution, which is desirable in cases where a pharmaceutically active ingredient is poorly soluble in the environment experienced in the respiratory tract, or where rapid release is desired. Nanoparticles, due to their very small size and large surface area, tend to dissolve rapidly, thus they have been employed for very hydrophobic materials to assist in more rapid dissolution, or where a rapid onset of action is required, such as with immediate release medications.
Pharmaceutically active materials may be delivered as nanoparticles alone, or as nanoparticle components incorporated into larger composite particles which act as delivery vehicles. For example, US 2003-0166509 describes spray drying of nanoparticles to form respirable larger sized particles. The nanoparticles are entrapped in a skeletal framework of precipitated excipient which makes up a larger particle of respirable size. The respirable particles are described as achieving a “sustained action” of drug upon delivery to a target site in the lung, as these composite particles degrade more slowly than a bare nanoparticle and release material in the entrapped nanoparticles as this degradation occurs. Generally, nanoparticles are spray dried from an aqueous suspension. In order to assure the homogeneity of the suspension feed stock, these processes typically include a surfactant in the liquid phase. The use of surfactants, although frequently used, may increase the risk of negative clinical side effects. Thus, removing the surfactant after particle production may be necessary, which increases costs or complexity in manufacturing, if such removal is possible. In spite of this, nanoparticles may be manufactured to be essentially crystalline, which could also avoid the instability and hygroscopicity issues generally found in amorphous particles.
WO 2012/051426 discloses aggregate nanoparticulate medicament formulations, processes of producing said formulations and uses thereof.
The present invention employs spray drying technology, which permits control and efficiency in generating improved aggregate particles, which may provide one or more of the following benefits: increased control of the physical and/or chemical properties of inhaled compositions, particularly crystallinity; increased manufacturing and/or delivery efficiency; greater flexibility in manufacturing, which allows use of a single platform of technology over a variety of pharmaceutically active materials and excipients; an improved drug delivery profile; longer shelf life; providing increased choice to formulators, healthcare providers and/or patients.